This invention relates to polymers which are prepared by living anionic polymerization and which contain a segment derived from a methacrylic ester and having a terminal functional group, a process for preparing the same, and compositions containing such polymers.
Conventionally, the anionic polymerization of xcex1, xcex2-unsaturated carbonyl compounds, typified by methyl methacrylate (MMA), is important in obtaining polymeric compounds having a controlled molecular weight or a controlled terminus, and has hence been investigated extensively. For example, in the anionic polymerization of MMA, molecular designs have usually been made by using an alkali metal alkyl (e.g., butyllithium or sodium naphthalene) as a living polymerization initiator. However, when an oxonium anion such as an alkali metal alcoholate is used as an initiator, MMA exhibits such low reactivity that, in the existing state of the art, MMA cannot be polymerized without resorting to various means (e.g., the use of a complexing agent such as a crown ether).
In the course of close investigation on the anionic polymerization characteristics of 2-hydroxyethyl methacrylate monomer whose hydroxyl group is protected with a trialkylsilyl group (hereinafter also referred to as ProHEMA), the present inventors have previously found that, in contrast to MMA and the like, this monomer can readily be polymerized with the aid of an alkali metal alcoholate because the monomer itself acts as a complexing agent (see Japanese Patent Laid Open No. 208628/""97). This has made it possible to introduce a greater variety of terminal groups into poly-HEMA, as contrasted with the prior art in which only radical poly-merization has been employed for this purpose, and also to carry out anionic polymerization without using alkali metal alkyls which have very high reactivity in anionic polymerization and are hence difficult to handle.
However, this process is limited to the synthesis of poly-HEMA having hydroxyl groups. As to the preparation of polymeth-acrylic esters having other functional groups, no polymerization process using an alkali metal alcoholate as an initiator has been known as yet.
Accordingly, an object of the present invention is to provide polymers which not only have a functional group at an end of the polymer, but also have any of various functional groups other than trialkylsiloxy groups in the ester residues derived from an MMA ester (i.e., the portions derived from an alcohol).
As a result of close investigation on the mechanism of this anionic polymerization reaction, the present inventors have now found that a methacrylic ester monomer having an electron-donating substituent group bonded to a specific site of its ester residue can be specifically and easily polymerized with the aid of a potassium alcoholate. It has been confirmed that, if a cyclic ether (e.g., ethylene oxide) or a cyclic ester (e.g., a lactide or lactone) is previously reacted with this polymerization system, a living polymer chain is produced correspondingly and the polymer chain of the aforesaid methacrylic ester can be extended through the medium of this living polymer chain. Moreover, it has also been found that, if a cyclic ether (e.g., ethylene oxide) or a cyclic ester (e.g., a lactide or lactone) is allowed to coexist in this reaction system, such a monomer readily undergoes random copolymerization to yield a copolymer of a methacrylic ester having a functional group and a lactide or lactone. These represent new polymerization techniques for the preparation of polymeth-acrylic esters having functional groups at the ester sides, and provide a previously unknown method for the introduction of a terminal functional group.
Thus, according to the present invention, there is provided a polymer represented by the following formula (I) and containing a polymethacrylic ester segment having a terminal functional group. 
wherein
X is represented by the group
R1"Parenopenst"L"Parenclosest"p
in which
R1 is an unsubstituted or substituted straight-chain or branched C1-15 alkoxy group, an unsubstituted or substituted aryloxy group, or an unsubstituted or substituted aryl-C1-3 alkoxy group, and, when R1 is a substituted group, the substituent is a vinyl group, an acetal-forming group, a cyano group, an aldehyde group, a carboxyl group, an amino group, a C l-6 alkoxycarbonyl group, a C2-7 acylamide group, a tri(C1-6 alkyl)siloxy group having the same or different alkyl groups, a siloxy group, or a silylamino group,
the linkage group xe2x80x94Lxe2x80x94 is represented by the formula 
in which the R2 groups are the same or different C1-6 alkyl groups,
q is an integer in the range of 3 to 5, and
p is an integer in the range of 0 to 1,000;
Z represents the group 
in which R3 is hydrogen or a C1-6 alkyl group, A is NR6R7, 
P(OR8)3, SR9 or SH, r is 0 or 1, R6, R7 and R8 are the same or different C1-6 alkyl groups, R9 is a tri(C1-6 alkyl)silyl group, and B is a C1-6 alkyl group;
n is an integer equal to 0 or in the range of 5 to 10,000; and
m is a positive number of 5 to 10,000;
provided that the polymer is a random copolymer when n is other than 0.
Such polymers, in themselves, are useful as functional polymers in a wide technical field. Moreover, when the X group contains, for example, an ethylenically unsaturated polymerizable group, they can be used as macromonomers for the preparation of further polymers, or can provide further functional polymers with the aid of other functional groups. In particular, the polymers (i.e., copolymers) of formula (I) in which n is other than 0 contain a biodegradable segment in the polymer chain, they are not only widely useful as biodegradable plastics, but also can provide materials which are very useful as materials for cell technology (e.g., cell culture beds), matrix polymers for drug delivery systems, and the like.
When n is 0,L in the linkage group "Parenopenst"L"Parenclosest"p is xe2x80x94CH2CH2xe2x80x94Oxe2x80x94, and p is other than 0, the copolymers of formula (I) are block copolymers having a hydrophilic-hydrophobic polymer (or oligomer) segment, and can form polymer micelles, for example, in an aqueous medium. In this case, the coreusually consists of segments derived from a methacrylic ester, and the shell usually consists of segments derived from ethylene oxide. Accordingly, the present invention also provides such polymer micelles. These polymer micelles can carry hydrophobic drugs and negatively chargeable compounds (e.g., nucleic acids, anionic proteins and other anionic drugs) in the core thereof, and are hence useful as carriers for the delivery of drugs.
Thus, according of the present invention, there is also provided a polymer micelle composition comprising the aforesaid polymer micelles having a nucleic acid or anionic protein contained therein. Among nucleic acids, those being used as drugs or investigated for use as drugs (e.g., various antisense DNAs) are especially contemplated.
The above-described polymers of formula (I) may be efficiently prepared according to the following preparation process which constitutes another embodiment of the present invention. That is, according to the present invention, there is also provided a process for the preparation of a polymer of formula (II) which comprises the step of polymerizing an alkali metal alcoholate of the formula (II)
Xxe2x80x94Mxe2x80x83xe2x80x83(II)
wherein X is as defined for formula (I) and M is lithium, sodium, potassium, cesium or strontium, with a methacrylic ester of the formula (III) 
wherein Z is as defined for formula (I), and optionally with a lactone or lactide of the formula (IV)(a) or (b) 
wherein q and R2 are as defined for formula (I), optionally in the presence of an inert solvent.
Conventionally, it has been considered that some MMA esters are scarcely polymerized, or not polymerized at all, by anionic polymerization using a metal alcoholate as a polymerization initiator. Although it is not wished to be bound by theory, the reason why, among such MMA esters, the monomers of formula (IV) can be efficiently polymerized is believed to be that the reactivity of the alcoholate is enhanced, for example, by the complexing of the alkali metal cation of the polymerization initiator with the monomer as shown in the following formula. 
Thus, the polymerization can be made to proceed without using a highly reactive initiator such as butyllithium. Consequently, polymers having various functional groups in the X group and the Z group can be directly prepared.